HCV infection has reached epidemic levels worldwide, and has tragic effects on the infected patients. Presently there is no effective treatment for this infection and the only drugs available for treatment of chronic hepatitis C are various forms of alpha interferon (IFN-α), either alone or in combination with ribavirin. However, the therapeutic value of these treatments has been compromised largely due to adverse effects, which highlights the need for development of additional options for treatment.
HCV is a small, enveloped virus in the Flaviviridae family, with a positive single-stranded RNA genome of ˜9.6 kb within the nucleocapsid. The genome contains a single open reading frame (ORF) encoding a polyprotein of just over 3,000 amino acids, which is cleaved to generate the mature structural and nonstructural viral proteins. ORF is flanked by 5′ and 3′ non-translated regions (NTRs) of a few hundred nucleotides in length, which are important for RNA translation and replication. The translated polyprotein contains the structural core (C) and envelope proteins (E1, E2, p7) at the N-terminus, followed by the nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B). The mature structural proteins are generated via cleavage by the host signal peptidase. The junction between NS2 and NS3 is autocatalytically cleaved by the NS2/NS3 protease, while the remaining four junctions are cleaved by the N-terminal serine protease domain of NS3 complexed with NS4A. The NS3 protein also contains the NTP-dependent helicase activity which unwinds duplex RNA during replication. The NS5B protein possesses RNA-dependent RNA polymerase (RDRP) activity, which is essential for viral replication. Unlike HBV or HIV, no DNA is involved in the replication of HCV.
U.S. Patent Publication (US 2005/0009737 A1) discloses that 1-(2-deoxy-2-fluoro-2-C-methyl-β-D-ribofuranosyl)cytosine (14) is a potent and selective anti-HCV agent. Previously known synthetic procedures (Schemes 1-3) for this compound are quite inefficient, with very low overall yields and are not amendable to large-scale.



Previously known methods for the preparation of (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleosides, and its analogues, from D-xylose, cytidine, or uridine employed DAST or Deoxofluor® for the key fluorination reaction. However, DAST and Deoxofluor® are expensive, hazardous for industrial synthesis, and provide often unreliable results. Therefore, these alkylaminosulfur trifluorides are not suitable for industrial production.
As a part of an effort to find better fluorination conditions, it has been discovered that opening of a cyclic sulfate with non-alkylaminosulfur trifluoride fluorinating agents is an excellent way to synthesize the anti-HCV nucleoside, (2′R)-2′-deoxy-2′-fluoro-2′-C-methylcytidine. In addition, it was discovered that this novel synthetic route can be adopted to other nucleosides including the anti-HCV nucleoside, D-2-deoxy-2-fluoro-cytidine (Devos, et al, U.S. Pat. No. 6,660,721), anti-HBV nucleosides, D and L-2′,3′-didehydro-2′,3′-dideoxy-2′-fluoro-nucleosides (Schinazi, et al, U.S. Pat. No. 6,348,587) (I and II, FIG. 3) as well as other 2′-substituted nucleosides such as D- and L-FMAU (Su, et al., J Med. Chem., 1986, 29, 151-154; Chu, et al., U.S. Pat. No. 6,512,107).
What is needed is a novel and cost effective process for the synthesis of 2′-C-alkyl-2′-deoxy-2′-substituted-D-ribopyranosyl nucleosides that have activity against HCV.